PROJECT SUMMARY The heterogeneity of genetic etiology and the corresponding neural complexity of schizophrenia have rendered the task of understanding disease pathophysiology and developing new improved treatments rather inauspicious. In light of this complexity there is need to identify convergent molecular and neural substrates that can serve as entry points to prevent or reverse disease progression. Along the same lines, identification of mutations or variants that confer protection against disease by disabling protein function via loss-of-function (LoF) effects, akin to those of a therapeutic agent, hold great promise for devising therapeutic schemes to restore or prevent some or all of disease symptoms. During the first iteration of this grant, we characterized the microRNA dysregulation in a model of the 22q11.2 deletion, one of the strongest genetic risk factor for schizophrenia [Df(16)A+/- mice]. We found that postnatal brain upregulation of Mirta22/Emc10, an inhibitor of neuronal maturation, represents the major transcriptional effect of the 22q11.2-associated microRNA dysregulation. Mice where the Df16(A) deficiency is combined with a LoF Mirta22 allele show a profound rescue of core SCZ-related deficits such as sensorimotor gating deficits, working and social memory deficits, as well as several of the underlying synaptic and cellular deficits. Thus several key disease alterations observed in Df(16)A+/? mice can be attributed to the abnormally sustained inhibitory influence of elevated Mirta22 levels. Building on these findings, this competitive renewal aims to elucidate further the nature of neural substrates underlying the protective influences of Mirta22 LoF mutations, compare the effects of normalizing Mirta22 levels during neonatal, adolescent and adult time periods using conditional genetic manipulations in mouse models (including the use of new therapeutic modalities of translatable value) and determine the relevance of our mouse results in human disease neurons. Determining when during the lifespan Mirta22 normalization is most effective at reversing disease phenotypes will be crucial for determining its potential use as a therapeutic target. !